The Emerging Role of N-Methyl-D-Aspartate (NMDA) Receptors in the Cardiovascular System: Physiological Implications, Pathological Consequences, and Therapeutic Perspectives

Abstract

N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ion channels that are activated by the neurotransmitter glutamate, mediate the slow component of excitatory neurotransmission in the central nervous system (CNS), and induce long-term changes in synaptic plasticity. NMDARs are non-selective cation channels that allow the influx of extracellular Na+ and Ca2+ and control cellular activity via both membrane depolarization and an increase in intracellular Ca2+ concentration. The distribution, structure, and role of neuronal NMDARs have been extensively investigated and it is now known that they also regulate crucial functions in the non-neuronal cellular component of the CNS, i.e., astrocytes and cerebrovascular endothelial cells. In addition, NMDARs are expressed in multiple peripheral organs, including heart and systemic and pulmonary circulations. Herein, we survey the most recent information available regarding the distribution and function of NMDARs within the cardiovascular system. We describe the involvement of NMDARs in the modulation of heart rate and cardiac rhythm, in the regulation of arterial blood pressure, in the regulation of cerebral blood flow, and in the blood–brain barrier (BBB) permeability. In parallel, we describe how enhanced NMDAR activity could promote ventricular arrhythmias, heart failure, pulmonary artery hypertension (PAH), and BBB dysfunction. Targeting NMDARs could represent an unexpected pharmacological strategy to reduce the growing burden of several life-threatening cardiovascular disorders.

Research progress and perspectives of N-methyl-D-aspartate receptor in myocardial and cerebral ischemia-reperfusion injury: A review

“…NMDAR is extensively distributed in cardiac tissue and plays a crucial role in regulating a range of physiological and pathological mechanisms, including cardioprotection, preconditioning, postconditioning, arrhythmias, hypertrophy, and apoptosis. [18][19][20] Myocardial ischemia is characterized by a deficiency in oxygen and glucose, which hinders the production of ATP and promotes anaerobic glycolysis. Consequently, this metabolic shift leads to acidosis and the accumulation of lactate.…”

“…In renal IRI, the expression of NMDAR isoforms and subunits varies in different renal regions and cell types resulting in different sensitivities and severities of renal IRI, and blockade of NMDAR can attenuate renal IRI and protect renal function and structure. [ 17 ] Especially in the cardiovascular system, studies have shown that NMDAR is detected and expressed throughout the cardiovascular system in both the physical and pulmonary circulation, such as the conduction system, cardiomyocytes, pachyderm fibers, sinus node, etc, [ 18 ] and plays different roles.…”

“…This, in turn, triggers inflammatory reactions, enhances the adhesion and infiltration of leukocytes, releases inflammatory mediators and cytokines, influences gene expression, and modulates cellular processes such as the cell cycle, apoptosis, and autophagy. [ 18 ] The involvement of NMDAR in the pathogenesis of myocardial IRI has been substantiated through multiple investigations. [ 23 – 25 ] Studies have demonstrated that the NMDAR antagonist MK-801 has the potential to decrease the extent of myocardial IRI, enhance cardiac function, and reduce the apoptosis rate and levels of free radicals in cardiomyocytes.…”

“…The toxicity of glutamate in cells and tissues after resuscitation is not immediately alleviated and can even worsen the injury. [ 18 , 41 , 42 ] NMDAR is widely expressed in the brain, mediating various physiological and pathological processes, such as synaptic transmission, learning and memory, neurogenesis, neuroprotection, and neurodegeneration. [ 43 , 44 ] During cerebral ischemia, hypoxia, and glucose deprivation lead to impaired ATP production and increased anaerobic glycolysis, resulting in acidosis and accumulation of lactate.…”

Intracellular Ca2+ signalling: unexpected new roles for the usual suspect

“…An additional mechanism that enriches the versatility of intracellular Ca 2+ signalling is represented by the spatial location of the Ca 2+ sources, which can be physically coupled to different Ca 2+ -dependent decoders ( Berridge et al, 2003 ; Bagur and Hajnoczky, 2017 ; Ong et al, 2019 ; Barak and Parekh, 2020 ). Environmental cues generate a complex choreography of intracellular Ca 2+ signals ( Berridge et al, 2003 ; Clapham, 2007 ), whose spatio-temporal malleability enables one single ion messenger to control as many different functions as fertilization ( Moccia et al, 2006 ), cell cycle ( Lim et al, 2003 ) and proliferation ( Faris et al, 2019 ; Faris et al, 2022 ), migration ( Fiorio Pla et al, 2012 ; Zuccolo et al, 2018b ), differentiation ( Maione et al, 2022 ), contraction ( Bers, 2008 ; Landstrom et al, 2017 ), metabolism ( Patella et al, 2015 ), angiogenesis ( Bernardini et al, 2019 ; Moccia et al, 2019b ; Scarpellino et al, 2020 ), vasculogenesis ( Moccia et al, 2012 ; Moccia et al, 2013 ; Zuccolo et al, 2018a ), and, more recently, neurovascular coupling ( Negri et al, 2021c ; Soda et al, 2023 ). The multifaceted nature of intracellular Ca 2+ signalling can be further appreciated by recalling that, depending on the Ca 2+ source and on the Ca 2+ -dependent target, an increase in [Ca 2+ ] i may induce opposing cellular responses, e.g., proliferation ( Faris et al, 2022 ) and apoptosis ( Astesana et al, 2021 ; Faris et al, 2023 ), vascular smooth muscle cell contraction ( Knot and Nelson, 1998 ) and relaxation ( Nelson et al, 1995 ), neuronal depolarization ( Menigoz et al, 2016 ) and hyperpolarization ( Tiwari et al, 2018 ), long-term potentiation ( Ezra-Nevo et al, 2018 ; Soda et al, 2019 ; Locatelli et al, 2021 ) and long-term depression ( Hirano, 2013 ).…”